Formal synthesis of (+)-anatoxin-a by asymmetric [2+2] cycloaddition

Article abstract of DOI:10.1055/s-2005-868482

A formal asymmetric synthesis of (+)-anatoxin-a, a neurotoxic alkaloid from Anabaena flos aquae, has been achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether.

Full text of DOI:10.1055/s-2005-868482

1328
LETTER
Formal Synthesis of (+)-Anatoxin-a by Asymmetric [2+2] Cycloaddition
F
ormal Synthesis of (+
a
)-Anatoxin
u-a ro Neves Muniz, Alice Kanazawa,* Andrew E. Greene
Université Joseph Fourier, Chimie Recherche, LEDSS, BP 53X, 38041 Grenoble Cedex, France
Fax +33(4)76514494; E-mail: Alice.Kanazawa@ujf-grenoble.fr
Received 10 March 2005
NH
Abstract: A formal asymmetric synthesis of (+)-anatoxin-a, a neu-
COCH3
rotoxic alkaloid from Anabaena flos aquae, has been achieved
through a highly diastereoselective [2+2] cycloaddition of dichlo-
roketene with a chiral enol ether.
(+)-anatoxin-a (1)
Key words: N-acyliminium ion, asymmetric synthesis, cycloaddi-
tion, chiral enol ether, dichloroketene
Figure 1
The [2+2] cycloaddition of dichloroketene (DCK)1 with
chiral enol ethers provides access to diastereomerically
enriched a,a-dichlorocyclobutanones,2 which in turn can
be easily converted into g-lactams by Beckmann ring ex-
pansion. These lactams have proven to be valuable inter-
mediates for the synthesis of a variety of nitrogen-
containing natural products, such as amino acids, pyrro-
lidines, pyrrolizidines, and indolizidines (Scheme 1).3
(Scheme 2). This chiral alcohol was transformed with
potassium hydride and trichloroethylene into the dichlo-
roenol ether 2b in 76% yield.7 Treatment of 2b with n-bu-
tyllithium, followed by 4-pentenyl triflate, provided ynol
ether 3a, which was directly submitted to controlled hy-
drogenation in the presence of Pd-BaSO4 and 1-hexene in
pyridine7,8 to give enol ether 3b.
The [2+2] cycloaddition of this chiral enol ether with in
situ generated dichloroketene proceeded smoothly and
with the usual high level of facial discrimination (95:5, 1H
NMR) to afford dichlorocyclobutanone 4. Without purifi-
cation, this cycloadduct was submitted to Beckmann ring
expansion using Tamura’s conditions,9 followed by
dechlorination of the resultant a,a-dichlorolactam with
Zn-Cu,10 to give lactam 5 in 48% overall yield from
dichloroenol ether 2b (5 steps, 86%/step).
Cl
O
R
R’
Beckmann
DCK
Cl
R
* *
*RO
*RO
R’
I
II
(R*OH = chiral alcohol)
O
Cl
Cl
NH
R
An N-acyliminium–allylic silane cyclization was planned
for the construction of the bicyclic system.11 To this end,
lactam 5 was N-protected by reaction with methyl cyano-
formate (91%) and the resulting imide was partially re-
duced with lithium triethylborohydride to afford the
corresponding hemiaminal derivative in 92% yield. The
formation of the allylic silane 6 was best effected through
cross metathesis,12 the second-generation Grubbs’
catalyst13 in refluxing CH2Cl2 affording the desired mate-
rial in 74% yield. Cyclization was then readily accom-
plished by the action of formic acid in CH2Cl2 at 0 °C to
give bicycle 7a14 in 77% yield (2:1 mixture of epimers).
nitrogen-containing natural
products
* *
*RO
R’
III
Scheme 1
To further demonstrate the usefulness of this chemistry
for alkaloid synthesis, we undertook the preparation of
(+)-anatoxin-a (1).4 This skeletally unique alkaloid is one
of the most potent agonists of the nicotinic acetylcholine
receptor (nAChR) known. Since its isolation from strains
of a freshwater blue-green alga, Anabaena flos aquae
(Lyngb.) de Bréb, it has inspired many synthetic chem-
ists.5 However, most of the synthetic approaches to date
start from chiral-pool material. In this paper, we describe
the application of our asymmetric [2+2] cycloaddition
methodology for a formal synthesis of this neurotoxin.
The C-7 substituent in 7a was now excised via alcohol
7b15 (CF3CO2H, 78%) and iodide 7c16 [I2, imidazole,
(C6H5)3P, 76%] through reduction of the latter with tribu-
tyltin hydride. The resulting crude product 7d17 was sub-
mitted to Wacker oxidation18 to provide in 55% yield (2
25
On the basis of previous work in this laboratory,3 the S-
enantiomer of 1-(2,4,6-triisopropylphenyl)ethanol (2a)6
was chosen as the starting material for the synthesis
steps) the known methyl ketone 8 {[a]D –13.5 (c 1.1,
CH3OH)},19 whose spectral data were in excellent accord
with the values reported in the literature.20 As the conver-
sion of 8 into (+)-anatoxin-a (1) had already been effi-
ciently carried out by Skrinjar et al.,20 this completed a
formal total synthesis of the natural product.
SYNLETT 2005, No. 8, pp 1328–1330
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-868482; Art ID: G08205ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formal Synthesis of (+)-Anatoxin-a
1329
(3) (a) Nebois, P.; Greene, A. E. J. Org. Chem. 1996, 61, 5210.
(b) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org.
Chem. 1998, 63, 4660. (c) Delair, P.; Brot, E.; Kanazawa,
A.; Greene, A. E. J. Org. Chem. 1999, 64, 1383.
(d) Pourashraf, M.; Delair, P.; Rasmussen, M.; Greene, A. E.
J. Org. Chem. 2000, 65, 6966. (e) Rasmussen, M.; Delair,
P.; Greene, A. E. J. Org. Chem. 2001, 66, 5438. (f) Roche,
C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5, 1741.
(4) (a) Devlin, J. P.; Edwards, O. E.; Gorham, P. R.; Hunter, N.
R.; Pike, R. K.; Stavric, B. Can. J. Chem. 1977, 55, 1367.
(b) Carmichael, W. W.; Biggs, D. F.; Gorham, P. R. Science
1975, 187, 542.
OR
1
2
Ar
b
d
c
O
2a, R = H
b, R = ClC=CHCl
3 a, C-1,C-2 triple bond
b, C-1,C-2 double bond
a
O
Cl
O
Cl
O
NH
Ar
Ar
e, f
(5) (a) Mansell, H. L. Tetrahedron 1996, 52, 6025. (b) Oh, C.-
Y.; Kim, K.-S.; Ham, W.-H. Tetrahedron Lett. 1998, 39,
2133. (c) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999,
121, 3057. (d) Aggarwal, V. K.; Humphries, P. S.; Fenwick,
A. Angew. Chem. Int. Ed. 1999, 38, 1985. (e) Parsons, P. J.;
Camp, N. P.; Edwards, N.; Sumoreeah, L. R. Tetrahedron
2000, 56, 309. (f) Wegee, T.; Schwarz, S.; Seitz, G.
Tetrahedron: Asymmetry 2000, 11, 1405. (g) Mori, M.;
Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004,
45, 4397. (h) Brenneman, J. B.; Martin, S. F. Org. Lett.
2004, 6, 1469. (i) Brenneman, J. B.; Machauer, R.; Martin,
S. F. Tetrahedron 2004, 60, 7301.
(6) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M.; Greene, A.
E. Tetrahedron: Asymmetry 1996, 7, 2707.
(7) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74,
13.
(8) Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969.
(9) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1.
(10) Johnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J. Org.
Chem. 1985, 50, 114.
(11) (a) Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W.
N. Heterocycles 1987, 26, 75. (b) For a recent review of N-
acyliminium ion chemistry, see: Maryanoff, B. E.; Zhang,
H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431.
O
4
5
OH
NCO2CH3
Ar
g, h, i
j
Si(CH3)3
O
6
NCO2CH3
NCO2CH3
COCH3
o
n
1
7
R'
R' = OCH(CH3)Ar
R' = OH
7a,
b,
c,
8
k
l
R' = I
m
d, R' = H
Scheme 2 Reagents and conditions: a) KH, THF; trichloro-
ethylene (76%); b) n-C4H9Li, THF; 4-pentenyl triflate; c) H2, Pd–
BaSO4, 1-hexene, C5H5N; d) Zn-Cu, Cl3CCOCl, (C2H5)2O; e)
NH2OSO2C6H2(CH3)3, CH2Cl2; Al2O3, CH3OH; f) Zn-Cu, NH4Cl,
CH3OH (48% from 2b); g) n-C4H9Li, THF; NCCO2CH3 (91%); h)
LiB(C2H5)3H, THF (92%); i) CH2=CHCH2Si(CH3)3, 2nd-generation
Grubbs’ catalyst, CH2Cl2 (74%); j) HCO2H, CH2Cl2 (77%); k)
CF3CO2H, CH2Cl2 (78%); l) (C6H5)3P, I2, imidazole, C6H5CH3
(76%); m) (C4H9)3SnH, AIBN, C6H6, CH3OH; n) PdCl2, DMF, H2O
(55%, 2 steps); o) ref.20; Ar = 2,4,6-triisopropylphenyl.
(12) (a) Brümmer, O.; Rücker, A.; Blechert, S. Chem. Eur. J.
1997, 3, 441. (b) Connon, S. J.; Blechert, S. Angew. Chem.
Int. Ed. 2003, 42, 1900. (c) Vernall, A. J.; Adell, A. D.
Aldrichimica Acta 2003, 36, 93.
(13) Scoll, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(14) To a solution of 6 (600 mg, 1.10 mmol) in 18.0 mL of
CH2Cl2 at 0 °C was added dropwise 3.2 mL of formic acid.
The reaction mixture was stirred at 0 °C for 1.75 h and then
quenched with a sat. solution of aq NaHCO3 and extracted
with CH2Cl2. The organic phase was washed successively
with H2O and brine and dried over anhyd Na2SO4. The crude
product was purified by SiO2 chromatography (10–20%
diethyl ether in pentane) to afford 386 mg (77%) of 7, as a
2:1 mixture of isomers. Analytical data for the major isomer
of 7a: colorless oil; [a]D25 –84.3 (c 1.0, CHCl3). IR: 3070,
1704, 1608, 1449, 1400, 1098, 1081 cm–1. 1H NMR (300
MHz, CDCl3, two rotamers): d = 1.17–1.29 (m, 18 H), 1.44–
1.53 (m, 2 H), 1.52 (d, J = 6.8 Hz, 3 H), 1.68–1.81 (m, 4 H),
1.98–2.03 (m, 1 H), 2.32 (m, 1 H), 2.67–2.89 (m, 2 H), 3.12–
3.17 (m, 1 H), 3.62 (s, 3 H), 3.86 (m, 2 H), 4.09–4.32 (m, 2
H), 4.86–5.09 (m, 3 H), 5.86–6.17 (m, 1 H), 6.93 (s, 1 H),
7.03 (s, 1 H). 13C NMR (75.4 MHz, CDCl3, two rotamers):
d = 23.2, 23.4, 24.0, 24.5, 24.9, 25.0, 25.3, 27.6, 28.2, 28.4,
29.2, 31.7, 32.0, 34.1, 40.0, 40.9, 52.1, 52.4, 52.7, 52.9, 58.3,
58.7, 58.8, 66.0, 71.5, 74.1, 74.8, 112.6, 112.7, 120.6, 123.4,
133,1, 143.8, 144.2, 145.8, 145.9, 147.5, 149.0, 155.3,
155.6. MS (CI): m/z (%) = 456 (100) [MH+]. Anal. Calcd for
C29H45NO3: C, 76.44; H, 9.95; N, 3.07. Found: C, 76.46; H,
10.11; N, 2.81.
In summary, a highly diastereoselective [2+2] cycloaddi-
tion of dichloroketene with a chiral enol ether has been
used to access an unusual alkaloid, (+)-anatoxin-a (1). The
synthesis serves to expand the range of nitrogen-contain-
ing natural products that can be effectively reached
through application of this chemistry.
Acknowledgment
We thank Professor P. Dumy for his interest in our work. Financial
support from the Université Joseph Fourier and the CNRS (UMR
5616, FR 2607) is gratefully acknowledged.
References
(1) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159.
(2) Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26,
5525.
Synlett 2005, No. 8, 1328–1330 © Thieme Stuttgart · New York

1330
M. N. Muniz et al.
LETTER
(15) Compound 7b (2:1 mixture of isomers): IR: 3432, 3073,
1683, 1463, 1403, 1347, 1122, 1087 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.40–2.00 (m, 7 H), 2.24–2.28 (m, 1 H),
2.47–2.78 (m, 2 H), 3.60–3.70 (4 s, 3 H), 4.00–4.50 (m, 3 H),
4.70–5.10 (m, 2 H), 5.60–6.15 (m, 1 H). MS (CI): m/z (%) =
226 (100) [MH+].
(17) Compound 7d (2:1 mixture of isomers): IR: 3074, 1699,
1638, 1450, 1397, 1340, 1113 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.24–1.86 (m, 8 H), 1.94–2.06 (m, 1 H), 2.14–
2.27 (m, 2 H), 3.66 (br s, 3 H), 4.10–4.50 (m, 2 H), 4.85–5.10
(m, 2 H), 5.70–6.20 (m, 1 H).
(18) Tsuji, J. Synthesis 1984, 369.
(16) Compound 7c (2:1 mixture of isomers): IR: 3073, 1698,
1637, 1449, 1397, 1117 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.22–1.50 (m, 2 H), 1.60–1.80 (m, 4 H), 2.05–2.18 (m, 1
H), 2.38–2.53 (m, 1 H), 2.72–2.88 (m, 1 H), 3.73 (s, 3 H),
4.14–4.54 (m, 2 H), 4.60–4.78 (m, 1 H), 4.88–5.10 (m, 2 H),
5.54–6.13 (m, 1 H). HRMS (CI): m/z calcd for C12H19NO2I
[M + 1]: 336.0461; found: 336.0471.
(19) A single isomer was obtained. The ee of 8 was estimated to
be 93% based on the rotation {[a]D25 –13.7 (c 1.0, CH3OH)]
and ee (94%) of the comparison material. This purity is
consistent with the observed diastereoselection (95:5) in the
cycloaddition and a subsequent small enrichment.
(20) Skrinjar, M.; Nilsson, C.; Wistrand, L.-G. Tetrahedron:
Asymmetry 1992, 3, 1263.
Synlett 2005, No. 8, 1328–1330 © Thieme Stuttgart · New York